Inherited defects in cardiac lipid metabolism are an important cause of inherited cardiomyopathy in sudden death in children and young adults. Recent studies also indicated that similar abnormalities in myocardial fatty acid utilization due to alterations in cardiac fatty acid utilization is poorly understood but may involve accumulation of toxic lipid intermediates within the cardiac myocyte. To investigate the molecular pathogenesis of cardiomyopathy due to abnormalities in cardiac lipid metabolism, we have begun to establish and characterize genetically engineered mouse lines with altered expression of enzymes and proteins involved in myocardial fatty acid import and utilization. Characterization of the cardiac phenotype of these mouse lines will allow us to develop murine models of metabolic cardiomyopathy and to test the hypothesis that accumulate of intracellular lipid plays a role in the genesis of heart failure and sudden death. The aims of this proposal include; 1) the development and characterization of mice with reduced expression of cardiac fatty acid oxidation (FAO) by altering the activity of transcription factors known to control the expression of this pathway to heart, 2) to produce and characterize mice with constitutively increased long-chain fatty acyl-CoA synthetase (FACS) in heart, 3) to characterize the cardiac phenotype of mice with diminished capacity for fatty acid utilization and/or increased fatty acid import under dietary and metabolic conditions known to precipitate heart failure in humans with inborn efforts in FAO, and 4) to characterize the cardiac phenotype of the mouse lines in response to physiologic conditions known to increase myocardial fatty acid utilization requirements. The results of these studies should provide significant insight into the role of perturbations in myocardial lipid metabolism and the pathogenesis of inherited and acquired forms of heart failure.